During migration from the blood stream to the tissue, immune cells including leukocytes pass through activated endothelial cells to induce immune responses, and many cell adhesion molecules (CAMs), such as integrins, selectins, ICAMs (intracellular adhesion molecule) and VCAMs (vascular cell adhesion molecule), are involved in the adhesion of leukocytes to endothelial cells and their migration to the tissue. Cell adhesion molecules are functionally divided into selectins involved in interaction between leukocytes and endothelial cells, integrins involved in adhesion of leukocytes to endothelial cells, and immunoglobulins such as ICAM and VCAM. These cell adhesion molecules play important roles in many physiological responses such as immune responses, inflammation, and thrombosis.
VCAM-1 is one of the vascular endothelial cell adhesion molecules, which interacts with integrin (VLA-4) expressed on the surfaces of most leukocytes, excluding neutrophils. VCAM-1 is expressed by inflammatory signals, and induces attachment of leukocytes to the vascular endothelial cells and the subsequent transendothelial migration of leukocytes into the damaged tissue.
Despite recent attention to VCAM-1-VLA-4 interaction, the development of a neutralizing antibody to VCAM-1 has not been actively studied. Although M/K-2.7, a monoclonal antibody to mouse VCAM-1, has recently been developed and shows an inhibitory effect on arthritis in collagen-induced arthritis mouse model, the antibody is specific only to mouse model, and thus the usefulness of the antibody should be further tested for clinical application.
Further, VCAM-1 consists of seven IgG-like domains and its domains 1 and 4 are substantially involved in binding with its ligand, integrin (α4β1 or α4β7) (1995, PNAS, 92:p5714; 1995, The journal of immunology, 155: p3135 et al.).
In this regard, there is an urgent need to develop a fully human monoclonal antibody which inhibits the interaction between VCAM-1 antigen and integrin to effectively inhibit adhesion and transmigration of leukocytes to endothelial cells, and minimizes the risk of immunogenicity.